Title: Dispelling the 'Law of Wiechers' and Maximizing Actives Delivery

Perhaps the highest level of arrogance a cosmetic scientist can display is to name a law after himself. However, this law was not named by me, it was named by my friend and colleague Jonathan Hadgraft, PhD, emeritus professor of biophysical chemistry for the department of pharmaceutics at the University of London's School of Pharmacy. This column was written on Dec. 16, 2010, on Hadgraft's 60th birthday; therefore, this column is in honor of him.

Hadgraft and his friend Richard H. Guy, PhD, professor of pharmaceutical sciences at the University of Bath's department of pharmacy and pharmacology, were the “enfants terribles” of the skin delivery field. At every conference that discussed skin delivery, the two arrived with something novel, and each time they were right about what they stated. These two gentleman peeled away the secrets of skin delivery like the rings of an onion, but without a tear. The two revolutionized the skin delivery of topically applied drugs.

My first memories of Hadgraft (and Guy) go back to 1987 at the second American Association of Pharmaceutical Scientists (AAPS) Congress in Boston. I was presenting my first scientific poster on the percutaneous absorption of azone, a skin penetration enhancer. As a young doctorate student, I was lucky that azone was such a promising skin penetration enhancer. It always guaranteed visitors at my poster, which resulted in a constant crowd.

Upon return from lunch one afternoon, there were two men debating in front of my poster. I asked what the debate was about and if I could assist in resolving the obvious dispute. At this moment, their name tags revealed them as the young but famous professors: Hadgraft from Cardiff University and Guy of the University of California. I felt stupid offering two of the most famous men in skin delivery my advice but they included me into their discussion as if nothing had happened. By now I have forgotten what the discussion was all about, in the same way that back then I forgot to ask for their autographs.

We’ve continued to meet over the years and in 2007, Hadgraft offered me a visiting professorship at the University of London's School of Pharmacy, where he moved to from Cardiff via Greenwich University in 2004. During one of my recent presentations there on formulating for efficacy, he advised the students not to forget the "Law of Wiechers in Cosmetics." In response, my expression shifted to looking just as puzzled as all the students, and as clueless as you may look right now.

Hadgraft explained, “Every active in cosmetics needs to be included at a level of 3%. That is the 'Law of Wiechers in Cosmetics.' It doesn’t make any difference what the active does or doesn’t do, the level is always 3%.”

I quickly realized that he was right. Almost every supplier tells the formulator that his active ingredient must be included at 3%. If the molecule is too active, it is diluted in such a way that 3% of a dilution must be added.

Hadgraft continued, “Wiechers [also] has told you to formulate an active ingredient at a level close to the maximum solubility limit in that vehicle to get close to maximum delivery, which is correct. [But] why, then, is it that the 'Law of Wiechers' dictates that every cosmetic active needs to be formulated at 3%? It is wrong!"

There Hadgraft and I agreed again, but I wondered why would he name this unwritten law in cosmetics after me. Upon further discussion, Hadgraft argued that in pharmaceutics and cosmetics, when scientists have no idea how to deliver a drug into the skin, they add it at a level that has been shown, in in vitro skin penetration experiments, to deliver the drug in reasonable quantities. Then they make a series of formulations containing smaller (and sometimes higher) concentrations to create pharmaceutical formulations with more or less efficacy.

Topical corticosteroids are a typical example of this approach but in cosmetics, he argued, it is even worse. In cosmetics, 3% should always be the amount of active although cosmetic manufacturers always formulate with less. Consumers then complain that cosmetics are not effective and according to suppliers, this is because the active amount is too small. To this point, Hadgraft argued, “Only we know that a formulator can make a 10% formulation that does not deliver at all and a 0.1% formulation that delivers perfectly. Why are we, plus a handful of skin delivery scientists, the only people to understand this?”

Hadgraft is right, as he probably has been every time for the last 40 years when talking about skin delivery. A formulator can create a 10% formulation that does not work and an 0.1% formulation that does—it depends on the solubility of the active ingredient in a formulation. The formulator should always formulate close to the maximal solubility of the active ingredient in their formulation. This is when the formulator has the maximum driving force for diffusion, or as the skin delivery scientist likes to call it, maximal thermodynamic activity.

A formulator can make a 3% solution of an active in solvent X where the maximum solubility is 3.3%, and another of 2% in solvent Y where the maximum solubility is 2.2% and the skin delivery will be the same. If this is an emulsion and the molecule is lipid-soluble, the formulator can reduce the oil phase, keeping the concentration the same without losing skin delivery since the percentage of maximum solubility is not changed.

How do suppliers know that the maximum solubility of their active in a formulation is always just above 3%? They do not; therefore, any in-use level recommendation cannot be used. It may be 3% for some specific systems, but other systems can easily be created in which the maximum solubility is lower, thereby reducing the concentration of the active in the formulation without losing the efficacy.

Hold your breath; it gets worse. Suppliers of cosmetic ingredients are keen on selling a nicely dissolved active that is easier to use, they say, and this is probably true. A formulator can then add the 3% active but what does the supplier use as a solvent? They use something in which the active is soluble but with the addition of that solvent to the formulation, the total solubility of the active in the formulation is increased, which reduces the skin penetration of the active ingredient. In other words, this solvent may indeed be easier for the formulator in the production process but it reduces the skin delivery of the active.

The supplier's answer is often to add more active, which makes the formulator add more solvent. This results in a higher solubility of the active and even less skin delivery. Supplying actives in a good solvent is just as helpful as the recommendation that you need to add 3% to your formulation. Once this science is understood, the ridiculous nature of the "Law of Wiechers" in cosmetics is realized.

Why Hadgraft calls this the "Law of Wiechers" is still beyond my comprehension but if it helps formulators to deliver their actives better, it is fine with me. Then my contribution to cosmetic science will not have been in vain. In the last 35 years, Hadgraft has already done more for cosmetic science than he can ever realize; naming a bit of non-science, aka nonsense, after me is probably the latest—but I am sure I will survive.

To my friend and colleague, congratulations on your 60th birthday. This column is to thank you for all your contributions to skin delivery science and cosmetic science. But explain one thing to me: Why do you love lukewarm British beer? After all, the level of ethanol in that stuff is only 3%!